Pyrrolobenzodiazepines
Some pyrrolobenzodiazepines (PBDs) have the ability to recognise and bond to specific sequences of DNA; the preferred sequence is PuGPu. The first PBD antitumour antibiotic, anthramycin, was discovered in 1965 (Leimgruber, et al., J. Am. Chem. Soc., 87, 5793-5795 (1965); Leimgruber, et al., J. Am. Chem. Soc., 87, 5791-5793 (1965)). Since then, a number of naturally occurring PBDs have been reported, and over 10 synthetic routes have been developed to a variety of analogues (Thurston, et al., Chem. Rev. 1994, 433-465 (1994)). Family members include abbeymycin (Hochlowski, et al., J. Antibiotics, 40, 145-148 (1987)), chicamycin (Konishi, et al., J. Antibiotics, 37, 200-206 (1984)), DC-81 (Japanese Patent 58-180 487; Thurston, et al., Chem. Brit., 26, 767-772 (1990); Bose, et al., Tetrahedron, 48, 751-758 (1992)), mazethramycin (Kuminoto, et al., J. Antibiotics, 33, 665-667 (1980)), neothramycins A and B (Takeuchi, et al., J. Antibiotics, 29, 93-96 (1976)), porothramycin (Tsunakawa, et al., J. Antibiotics, 41, 1366-1373 (1988)), prothracarcin (Shimizu, et al, J. Antibiotics, 29, 2492-2503 (1982); Langley and Thurston, J. Org. Chem., 52, 91-97 (1987)), sibanomicin (DC-102)(Hara, et al., J. Antibiotics, 41, 702-704 (1988); Itoh, et al., J. Antibiotics, 41, 1281-1284 (1988)), sibiromycin (Leber, et al., J. Am. Chem. Soc., 110, 2992-2993 (1988)) and tomamycin (Arima, et al., J. Antibiotics, 25, 437-444 (1972)). PBDs are of the general structure:
They differ in the number, type and position of substituents, in both their aromatic A rings and pyrrolo C rings, and in the degree of saturation of the C ring. In the B-ring there is either an imine (N═C), a carbinolamine (NH—CH(OH)), or a carbinolamine methyl ether (NH—CH(OMe)) at the N10-C11 position which is the electrophilic centre responsible for alkylating DNA. All of the known natural products have an (S)-configuration at the chiral C11a position which provides them with a right-handed twist when viewed from the C ring towards the A ring. This gives them the appropriate three-dimensional shape for isohelicity with the minor groove of B-form DNA, leading to a snug fit at the binding site (Kohn, In Antibiotics III. Springer-Verlag, New York, pp. 3-11 (1975); Hurley and Needham-VanDevanter, Acc. Chem. Res., 19, 230-237 (1986)). Their ability to form an adduct in the minor groove, enables them to interfere with DNA processing, hence their use as antitumour agents.
In WO 93/18045, some of the present inventors disclosed the following compound (Example 6):
The final compound produced was a mixture of the E-, E-form, the Z-, Z-form and the E-, Z-forms as a result of the synthesis method used. Extrapolating from the last compound for which the amount of different geometric isomers was measured, the final compound would likely have the following proportions of geometric isomers:
Geometric isomers at C2/C2′Amount (%)E-, E-42E-, Z-46Z-, Z-12Gram-Positive Bacteria
Infectious diseases are a leading cause of mortality and morbidity worldwide. Our ability to treat effectively a range of bacterial infections rose dramatically following the introduction of penicillin and other antibiotics, but multi-drug resistance has emerged as a serious threat to efforts to continue to keep infectious diseases under control.
Two of the most serious pathogens associated with drug resistance are methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant enterococci (VRE).
MRSA has become one of the most problematic pathogens in humans not only in nosocomial but also recently in community-acquired infections (Tadashi Baba, et al., The Lancet, 359, 1819-1827 (2002); Enright, M. C., Current Opinion in Pharmacology, 3, 1-6 (2003)). S. aureus harmlessly colonises the nasal cavity of some 30-40% of the population and may also survive on dry skin for example on the hands. Health care workers and hospital staff may be carriers and may unwittingly infect patients under their care. S. aureus, an opportunistic pathogen, is of concern in immunocompromised people, prone to infection. It may infect many sites postoperatively if contaminated surgery equipment is used on, for example, open wounds. Blood, heart, bones and joints are also prime tissue-targets of infection. Furthermore toxic shock syndrome, pneumonia and food-poisoning contribute to the wide-spectrum of pathogenicity this organism causes. S. aureus infections had been treated successfully with potent antibiotics in the past, however the emergence of multi-drug resistance has limited opportunities to successfully treat these infections.
VRE account for nosocomial infections and is currently a major problem of many healthcare institutions. Although there are several members in the Enterococcus family, only two are usually associated with the high morbidity and mortality in hospitals, namely E. faecalis and E. faecium. Enterococci are part of the normal gastrointestinal tract flora and are carried by healthy individuals. Although many hospital patients may be colonised with VRE, this does not necessarily lead to infection. VRE infections tend to occur in immunocompromised and seriously ill patients such as those in intensive care units. It has been difficult to establish exactly how much VRE contributes to mortality rates as there are usually many other concomitant infections present in infected patients. In many cases, severe underlying diseases in patients are likely to be the sole cause of death not linked to VRE. The tissues affected are usually the urinary tract, surgical sites, blood and abdominal sites. In addition, endocarditis is a serious infection resulting as a consequence of VRE bacteraemia. The mode of transmission of VRE is similar to that of MRSA. Direct skin-to skin contact with colonised health care workers and contaminated surgical equipment seem to be the leading factors. It appears that the bacteria not only survive on the hands and arms of health workers but may also remain on bed linen and hospital beds as well as other surrounding objects for several days.